Drug Discovery & Synthesis Core

Gunda I. Georg, PhD Professor & Department Head Department of Medicinal Chemistry Robert Vince Endowed Chair Mcknight Presidental Chair in Medicinal Chemistry. University of Minnesota	Ernst Schonbrunn, PhD Associate Professor, Drug Discovery Department Scientific Director, Structural Biology Core H. Lee Moffitt Cancer Center and Research Institute School of Medicine Department of Oncological Sciences University of South Florida
	Derek Hook, PhD Director of the High Throughput Screening Laboratory for the Institute for Therapeutics Discovery & Development University of Minnesota

Drug Discovery & Synthesis Core, DDS supports the interdisciplinary U54 center with the expertise to discover, design, synthesize, and develop male contraceptive agents. In a highly collaborative manner with the PIs of this center,
The DDS and the NICHD will optimize hit and lead compounds for potency, selectivity, and pharmaceutical properties in preparation for clinical trails.

The long-term goal of this center is the development of non-hormonal male contraceptive agents. Thus, we have selected, based on the approved research projects, targets for drug discovery that are important for spermatogenesis, spermiation, motility, and/or capacitation. The central research hypothesis for the core is that small molecule inhibitors of each of the targets can be discovered, optimized, and investigated in vitro and in vivo with the ultimate goal to bring one or more agents towards clinical trials. The expertise and environment for drug discovery provided by the core is also excellent and provides unique facilities that are not often found at universities such as high throughput screening laboratories (UMN and KU), a combinatorial chemistry laboratory (UMN), a large-scale synthesis laboratory (UMN), an Office for Therapeutics Discovery and Development (KU), and a common Good Manufacturing Procedures (c-GMP) synthesis facility (UMN).

Objective 1: Identify inhibitors for sperm-specific targets by high throughput screening and by screening of targeted libraries. In collaboration with the project PIs, we have developed assays that are suitable for high throughput screening. A compound library of over 200,000 compounds and/or smaller targeted libraries will be screened to identify small molecule inhibitors of the target proteins.

Objective 2: Determine protein-inhibitor interactions by protein X-ray  crystallography.
Target proteins have been co-crystallized with lead compounds and the structure of the protein-hit complex(es) determined at atomic resolution. The structural data is used for structure-based drug design to optimize hit compounds for potency and selectivity and for in silico screening.

Objective 3: Optimize screening hits for potency and selectivity. Small molecules are optimized for potency and selectivity, using structure-based drug design and other rational design medicinal chemistry principles. These studies are carried out in close collaboration with the project PIs and the Drug Development Core. Compounds are prepared, tested and then further optimized with the goal to generate single digit nanomolar inhibitors that posses about 1000-fold selectivity and aqueous solubility of >100 μg/ml.

Objective 4: Develop lead compounds for preclinical and clinical evaluation. In collaboration with the KU Office of Drug Therapeutics and the NICHD we will optimize the pharmaceutical properties of lead compounds in preparation for clinical trails. We also provide large-scale amounts of lead compounds for animal studies to NIH and for U54 investigators. Our approach toward the discovery and development of non-hormonal male contraceptive agents is innovative because we have identified several highly promising targets that have not been explored for drug discovery before. We are bringing state-of-the-art drug discovery methods to bear on these projects and are looking forward to working with the other U54 centers and providing them with drug discovery and development resources and expertise that are rarely available at academic institutions.

Our goal is to identify small molecule inhibitors for each of the targets, co-crystallize small molecule inhibitors with the target proteins, use structural information about protein-inhibitor interactions for drug design. The screening hits will have been optimized for potency, selectivity, and pharmaceutical properties and we expect that at least one optimized lead compound will have been selected for clinical trials and will ultimately be commercialized for male contraception.